Inflammatory arthritis is a prominent clinical manifestation in diverse autoimmune disorders including rheumatoid arthritis (RA), psoriatic arthritis (PsA), systemic lupus erythematosus (SLE), Sjogren's syndrome and polymyositis.
RA is a chronic inflammatory disease that affects approximately 0.5 to 1% of the adult population in northern Europe and North America. It is a systemic inflammatory disease characterized by chronic inflammation in the synovial membrane of affected joints, which ultimately leads to loss of daily function due to chronic pain and fatigue. The majority of patients also experience progressive deterioration of cartilage and bone in the affected joints, which may eventually lead to permanent disability. The long-term prognosis of RA is poor, with approximately 50% of patients experiencing significant functional disability within 10 years from the time of diagnosis. Life expectancy is reduced by an average of 3-10 years.
Inflammatory bone diseases, such as RA, are accompanied by bone loss around affected joints due to increased osteoclastic resorption. This process is mediated largely by increased local production of pro-inflammatory cytokines, of which tumor necrosis factor-α (TNF-α) is a major effector.
In RA specifically, an immune response is thought to be initiated/perpetuated by one or several antigens presenting in the synovial compartment, producing an influx of acute inflammatory cells and lymphocytes into the joint. Successive waves of inflammation lead to the formation of an invasive and erosive tissue called pannus. This contains proliferating fibroblast-like synoviocytes and macrophages that produce proinflammatory cytokines such as TNF-α and interleukin-1 (IL-1). Local release of proteolytic enzymes, various inflammatory mediators, and osteoclast activation contributes to much of the tissue damage. There is loss of articular cartilage and the formation of bony erosions. Surrounding tendons and bursa may become affected by the inflammatory process. Ultimately, the integrity of the joint structure is compromised, producing disability.
B cells are thought to contribute to the immunopathogenesis of RA, predominantly by serving as the precursors of autoantibody-producing cells but also as antigen presenting cells (APC) and pro-inflammatory cytokine producing cells. A number of autoantibody specificities have been identified including antibodies to Type II collagen and proteoglycans, as well as rheumatoid factors and most importantly anti citrullinated protein antibodies (ACPA). The generation of large quantities of antibody leads to immune complex formation and the activation of the complement cascade. This in turn amplifies the immune response and may culminate in local cell lysis.
Current standard therapies for RA which are used to modify the disease process and to delay joint destruction are known as disease modifying anti-rheumatic drugs (DMARDs). Methotrexate, leflunomide and sulfasalazine are traditional DMARDs and are often effective as first-line treatment.
Biologic agents designed to target specific components of the immune system that play role in RA are also used as therapeutics. There are various groups of biologic treatments for RA including; TNF-α inhibitors (etanercept, infliximab and adalimumab), human IL-1 receptor antagonist (anakinra) and selective co-stimulation modulators (abatacept).
Rituximab is indicated for the treatment of moderate to severe RA in adult patients who have had an inadequate response to, or cannot tolerate, one or more TNF-α inhibitor therapies. It has been shown to be effective in the treatment of RA in patients refractory to treatment with anti-TNF therapy.
The Rituximab antibody is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen. Rituximab binds human complement and lyses lymphoid B-cell lines through complement-dependent cytotoxicity. Additionally, it has significant activity in assays for antibody-dependent cellular cyotoxicity. More recently, Rituximab has been shown to have anti-proliferative effects in tritiated thymidine-incorporation assays and to induce apoptosis directly. Other anti-CD19 and anti-CD20 antibodies have not been shown to have this activity.
Rituximab treatment has been shown to result in B cell depletion in peripheral blood, bone marrow and the synovium. However, not all patients refractory to treatment with anti-TNF therapy are responsive to Rituximab treatment. Current evidence on the efficacy of Rituximab relates primarily to rheumatoid factor, ACPA positive patients, although even within this population clinical responses are heterogeneous with only 60% achieving an ACR20 response within 6 months.
Rituximab is associated with various safety issues, especially infusion-related adverse events and is also very expensive, costing approximately $10,000 per treatment course.
There is thus a need for a method to predict whether a given RA patient is likely to respond to Rituximab treatment. There is also a need for alternative method of treatment for RA patients who are refractory to treatment with Rituximab.